Repurposing of Glatiramer Acetate to Treat Heart Diseases

Myocardial injury may ultimately lead to adverse ventricular remodeling and development of heart failure (HF), which is a major cause of morbidity and mortality worldwide. Given the slow pace and substantial costs of developing new therapeutics, drug repurposing is an attractive alternative. Studies of many organs, including the heart, highlight the importance of the immune system in modulating injury and repair outcomes. Glatiramer-acetate (GA) is an immunomodulatory drug prescribed for patients with multiple sclerosis. Here we report that short-term GA treatment improves cardiac function and reduces scar area in a mouse model of acute myocardial infarction, as well as in a rat model of ischemic HF. We provide both in vivo and in vitro mechanistic evidence indicating that in addition to its immunomodulatory functions, GA exerts beneficial pleiotropic effects, including cardiomyocyte protection and enhanced angiogenesis, mediated partially by extracellular vesicles carrying a pro-reparative cargo. Finally, as GA is a widely used drug with established efficacy and safety history, we conducted a small, prospective, randomized trial to determine its effect on patients admitted to the hospital with acute decompensated HF (ADHF). Strikingly, a short-term add-on administration of GA, resulted in marked reduction in the cytokine surge and NT-proBNP levels, both associated with acute HF exacerbations. Overall, these findings demonstrate the efficacy of GA in attenuating acute myocardial injury and modulating the inflammatory process in animal models and humans and highlight the potential of GA as a future therapy for a myriad of heart diseases. One Sentence Summary Glatiramer acetate promotes reparative processes in rodent models of cardiac injury and reduces the inflammatory process in ADHF patients. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT06003972 ### Funding Statement 179BThe study was supported by the following funding sources: 180BEuropean Research Council, ERC AdG grant no. 788194, CardHeal (E.T) 181BERC-PoC no. 899224, ReDHeaD (E.T) 182BEU Horizon 2020 Research and Innovation Programme REANIMA ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Ethics committee and national ethics committee of Israeli Ministry of Health gave their ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors